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Utilization of the Human Genome Sequence Localizes Human Papillomavirus Type 16 DNA Integrated into the TNFAIP2 Gene in a Fatal Cervical Cancer from a 39-Year-Old Woman

Albert Einstein College of Medicine/Montefiore Medical Center- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health, Bronx, New York 10461 [M. H. E., S. R., C. D. R., R. D. B.]; Albert Einstein Comprehensive Cancer Research Center, Bronx, New York 10461 [Y. C., M. K. E-A., M. v R., S. R., C. D. R., R. D. B.]; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [N. C. P., J. A. D.]; Albert Einstein College of Medicine/Montefiore Medical Center, Department of Pathology, Bronx, New York 10461 [A. S. K.]; and Albert Einstein College of Medicine, Departments of Pediatrics, Microbiology and Immunology, Epidemiology and Social Medicine, Bronx, New York 10461 [R. D. B.]

Purpose: The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman.

Experimental Design: An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence.

Results: HPV 16 DNA (3826 bp) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene.

Conclusions: On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 DNA integrates into the host genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites.

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